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Introduction
• Lipids
– Poorly soluble
– Multiple uses
– Components of cellular membranes
– Synthesis:
• Water soluble precursor membrane-associated
intermediate membrane lipid products
• Fatty acids
– Oxidized to release energy for cellular functions
– Stored and transported primarily as triglycerides
– Precursors of phospholipids
• Cholesterol
– Precursor for steroid hormones and other biologically active
lipids; function in cell-cell signaling
18.1 Phospholipids and Sphingolipids:
Synthesis and Intracellular Movement
• additional membrane is needed for cell expansion; synthesize new
membranes only by expansion of existing membranes
• the basic structural and physical properties of membranes are
determined by their lipid components—principally phospholipids,
sphingolipids, and sterols such as cholesterol
• early steps occur in cytoplasm; final steps catalyzed by enzymes
bound to preexisting cellular membranes and products incorporated
(must be properly distributed)
A. Fatty acids are precursors for phospholipids and other
membrane components
• fatty acids anchor proteins to membranes and play role in reg. of
membrane synthesis
• Fatty acid composed of a long hydrocarbon chain with a carboxyl
group at one end
• Saturated—single bonds; unsaturated—one or more double bonds
• Acetyl-CoA carboxylase and fatty acid synthase: make saturated
fatty acids with 14 or 16 carbons.
• Desaturase enzymes located in ER introduce double bonds at
specific positions in some fatty acids; these double bonds create a
kink
• Fatty acids derived from de novo synthesis from acetyl CoA and
from the enzymatic hydrolysis of triglycerides
• Triglycerides—the primary form in which fatty acids are stored and
transported
three fatty acids and glycerol combine to form a triglyceride
B. Unesterified Fatty acids move within cells bound to
small cytosolic proteins
• commonly bound by fatty acid-binding proteins (FABPs) which
facilitate intracellular movement of many lipids
• Contain a hydrophobic pocket lined by beta sheets where a longchain fatty acid can fit into this pocket and interact noncovalently
with the surrounding protein
C. Incorporation of Fatty acids into membrane lipids
takes place on organelle membranes
• fatty acids are not directly incorporated, first converted in eukaryotic cells into CoA
esters. Diacyl glycerophospholipids are then synthesized from the CoAs
• plasmaologen—different type of glycerol-derived phospholipids found in animals
cells and some anaerobic microorganisms; may influence the movement of
cholesterol
– reservoir of arachidonate—precursor for large group of signaling molecule called
eicosanoids. Regulated release of arachidonate plays a rate-determining role in signaling
pathways
– platelet-activating factor (PAF)—signaling molecule that plays role in inflammatory
response due to tissue damage or injury
• Sphingolipids—another major group of membrane lipids
– Derivatives of sphingosine—amino alcohol that contains a long, unsaturated hydrocarbon
chain; made in the ER but can take place in mitochondria
– important signaling molecules in cell growth, proliferation, endocytosis, resistance to
stress, and apoptosis
– after synthesis in the Golgi, transported in vesicle-mediated mechanisms to other cellular
compartments.
D. Flippases move phospholipids from one
membrane leaflet to the opposite leaflet
• Phospholipids are asymmetrically distributed in the 2 leaflets of the
cytosol. Spontaneous flip-flop from one leaflet to the other only
very slowly, but can rapidly diffuse laterally in the plane of the
membrane.
• Flippases play a key role; integral membrane protein that facilitate
the movement of phospholipid molecules from one leaflet to
another; ABCB4
• Processes of phospholipids in membranes:
–
–
–
–
–
flip-flopping between leaflets
lateral diffusion
membrane fission
ongoing covalent remodeling
Intracellular movement of phospholipids from one membrane to a different
one
18.2 Cholesterol:
A multifunctional Membrane Lipid
• eukaryotic cells require sterols
• (cholesterol—critical for intercellular signaling and other functions)
A. Cholesterol is synthesized by enzymes in the
Cytosol and ER Membrane
B. Many bioactive molecules are made from cholesterol and
its biosynthetic precursors
a.
b.
c.
d.
Bile acids—in the liver
Used in arthropods for membranes and ecdysteroid
hormones
Added to Hedgehog protein—a key signaling molecule
in embryonic development
Intermediates in the cholesterol pathway also serve as
precursors for biologically active molecules
C. Cholesterol and phospholipids are transported between
organelles by golgi-independent mechanisms
-Finals steps take place primarily in the ER so requires one or more intracellular transport processes
-Mechanisms of transport of cholesterol and phospholipids from their sites of synthesis to other membranes
independently of the Golgi-mediated secretory pathway
--Membrane-limited vesicles or other protein-lipid complexes
--Direct protein-mediated contact of ER or ER-derived membranes with membranes of other
organelles
--Small lipid-transfer proteins
-Steroidogenic acute regulatory protein (StAR)
--Encoded in nuclear DNA that controls the transfer of cholesterol from the outer mitochondrial
membrane to the cholesterol-poor inner membrane, where it undergoes the 1st steps in conversion into
steroid hormone
--Key regulated, rate controlling step in steroid hormone synthesis
--Contains N-terminal targeting sequence that directs the protein to the mitochondrial outer membrane
and a C-terminal START domain that has a cholesterol-binding hydrophobic pocket—promote
cholesterol transfer in cultured cells
-Niemann-Pick C1 (NPC1) protein
--Integral membrane protein located in the rapidly moving late endosomoal/lysosomal compartment
-- contains a sterol-sensing domain
--NPC1 is required for the normal movement of cholesterol between certain intracellular
compartments
Summary:
• 18.1—Phospholipids and sphingolipids: Synthesis and intracellular
movement
– Saturated and unsaturated fatty acids of various chain lengths are
components of phospholipids, sphingolipids, and triglycerides
– fatty acids are synthesized by water-soluble enzymes and modified by
elongation and desaturation in the endoplasmic reticulum (ER)
– The finals steps in the synthesis of glycerophospholipids, plamalogens,
and sphingolipids are catalyzed by membrane-associated enzymes
primarily in the ER
– each type of lipid is initially incorporated into the preexisting membranes
on which it is made
– most membrane phospholipids are preferentially distributed in either the
exoplastmic or the cytosolic leaflet. This asymmetry results in part from
the action of flippases such as ABCB4
Summary Cont.:
• 18.2—Cholesterol: A multifunctional membrane lipid
– the initials steps in cholesterol biosynthesis take place in the cytosol, whereas the last
steps are catalyzed by enzymes associated with the ER membrane
– the rate-controlling step in cholesterol biosynthesis is catalyzed by HMG-CoA
reductase, whose transmembrane segments are embedded in the ER membrane and
contain a sterol-sensing domain
– cholesterol itself and isoprenoid intermediates in its synthesis are biosynthetic
precursors of steroid hormones, bile acids, lipid-soluble vitamins, and numerous other
bioactive molecules
– considerable evidence indicates that vesicular trafficking through the Golgi complex
is not responsible for much cholesterol and phospholipid movement between
membranes. Golgi-independent vesicular transport, direct protein-mediated contacts
between different membranes, soluble protein carriers, or all three may account for
some interorganelle transport of cholesterol and phospholipids
– the StAR protein, which has a hydrophobic cholesterol-binding pocket, plays a key
role in moving cholesterol into the mitochondrion for steroid hormone synthesis
– the NPC1 protein, a large, multipass transmembrane protein, contains a sterol-sensing
domain similar to that in HMG-CoA reductase, NPC1 is required for the normal
movement of cholesterol between certain intracellular compartments
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